Nanoparticle Paclitaxel Research Articles

Efficacy from the phase 1 study of FID-007, a novel nanoparticle paclitaxel formulation, in patients with head and neck squamous cell carcinoma.

6042 Background: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) have limited treatment options after progression on first-line immunotherapy with or without platinum-based chemotherapy. Taxanes in this setting have historically demonstrated response rates around 14-27%. FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. This allows the drug to remain in solution until it can enter a cancer cell and preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. Preclinically, FID was more effective at lower or comparable taxane doses, including nab-paclitaxel. In the phase I study of FID, we determined 125 mg/m2 as the recommended phase 2 dose. Here we present updated safety and efficacy data with emphasis on pts with HNSCC. Methods: The study evaluated the safety, PK, and preliminary efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 160mg/m2 using a 3+3 dose escalation. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and < 3 prior lines of cytotoxic therapy. Results: 46 patients were enrolled, of which 9 had HNSCC (2 nasopharynx, 2 sinonasal, 3 oropharynx, 1 oral cavity, and 1 occult primary). Median age (range) was 60 (53-75). ECOG PS was 1 in all HNSCC pts. Median number of prior therapies was 3 (1-5) and all had received prior immune checkpoint inhibitor. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts included rash (72%), alopecia (52%), leukopenia (46%), pruritus (43%), neutropenia (41%), anemia (37%), fatigue (37%), nausea (28%), and anorexia (28%). Grade 3/4 TRAEs occurring in >1 pt were maculopapular rash (35%), neutropenia (20%), leukopenia (20%), anemia (17%), lymphopenia (7%), and febrile neutropenia (4%). No pts experienced > grade 2 peripheral sensory neuropathy; 20% experienced grade 1-2. Across all solid tumors, the overall response rate (ORR) was 17%. In patients with HNSCC, 5 (56%) had a partial response, 2 (22%) had stable disease, and 2 (22%) had PD. Three out of 5 HNSCC patients previously treated with a taxane achieved a partial response. Median duration of treatment was 4 months (1-15). Conclusions: FID demonstrates preliminary evidence of anti-tumor activity in heavily pre-treated HNSCC pts across different primary tumor sites, with an ORR 56%, including those with prior taxane exposure. A phase 2 study of FID with cetuximab in pts with HNSCC is planned to begin enrollment in 2024. Clinical trial information: NCT03537690 .

A phase 1 dose escalation/expansion study of FID-007, a novel nanoparticle paclitaxel formulation, in patients with solid tumors.

3026 Background: FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. In addition to allowing the drug to remain in solution until it can enter a cancer cell, the PEOX nanoparticle preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. In xenograft studies, FID reduced or limited tumor growth in multiple tumor types including lung, gastric, breast, pancreatic, and ovarian cancer. Preclinically, FID was more effective at lower or comparable taxane doses, including nab-paclitaxel, with fewer side effects. We present the first-in-human trial of FID. Methods: The study is evaluating the safety, PK, and efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 160mg/m2 using a standard 3+3 dose escalation design. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and ≤ 3 prior lines of cytotoxic therapy for advanced disease. Results: Thirty-six patients were treated across 7 dose levels. Median age was 61 (39-65). ECOG PS was 2 in 1 patient, 1 in 69% of patients. Median number of prior therapies was 2 (1-5). Median number of cycles was 2.5 (1-30). There were 2 DLTs of grade 3 rash at 100 mg/m2. Given the transient nature of the rash and response to topical therapy, DLT definition was modified to exclude grade 3 rash that lasts ≤ 7 days and 3 additional patients were treated at 100 mg/m2 which was deemed tolerable. There was 1 DLT of grade 4 WBC decrease at 125 mg/m2, and 1 DLT of G3 febrile neutropenia at 160 mg/m2. There was no MTD. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts were rash (64%), alopecia (56%), leukopenia (47%), pruritus (44%), neutropenia (42%), anemia (42%), fatigue (39%), nausea (33%), anorexia (31%), dysgeusia (25%) and peripheral sensory neuropathy (25%). Grade 3/4 TRAEs occurring in >1 pt were maculopapular rash (25%), anemia, neutropenia, and leukopenia (17% each). Of 36 evaluable patients, 7 (19%) had a partial response by RECIST 1.1 (pancreatic, biliary tract, and HNSCC) and 13 (36%) had stable disease. Three out of 4 HNSCC patients with PR had previously been treated with docetaxel. PK is linear and dose proportional. There is no paclitaxel accumulation after weekly dosing, and t1/2 is between 18-26 hours. Based on overall tolerability and PK, the dose of 125mg/m2 (dose level 6) has been chosen as RP2D. Conclusions: FID has a manageable safety profile and demonstrates preliminary evidence of anti-tumor activity in heavily pre-treated pts across different tumor types. No high-grade neuropathy has been noted to date. RP2D of FID is set at 125mg/m2. PK is linear, dose proportional and comparable to that of nab-paclitaxel. Clinical trial information: NCT03537690 .

Enhancing nanoparticle paclitaxel antitumor response through targeted inhibition of c-Met pathway by merestinib in gastric cancer models.

372 Background: Gastric adenocarcinoma (GAC) is the fifth most common malignancy and the third most common cause of cancer-related deaths worldwide. Combination chemotherapy regimens are commonly used to treat GAC, but the median survival time remains less than one year. Nanoparticle albumin-bound paclitaxel ( nab-paclitaxel, NPT), an approved treatment for breast cancer, non-small cell lung cancer and pancreatic cancer, has demonstrated high antitumor activity in previous GAC studies. Many growth factors and their receptors are overexpressed in GAC and have been implicated in its pathophysiology. Aberrant activation of the c-Met pathway has been reported in up to 50% of GAC patients. We hypothesize that merestinib, a small-molecule inhibitor of c-Met, with additional inhibition of Axl and DDR1/2 pathways, will have significant antitumor effects and will enhance nab-paclitaxel chemotherapy response in GAC preclinical models. Methods: GAC subcutaneous xenografts were established by injecting MKN-45 and SNU-1 cells in NOD/SCID mice to study treatment effects on tumor volume, tumor weight, net tumor growth, and mouse body weight. Immunohistochemistry analyses of xenograft tissues were performed using Ki67 and endomucin to examine tumor cell proliferation and microvessel density, respectively. Results: In vitro assays showed that nab-paclitaxel and merestinib decreased cell proliferation in all three GAC-associated cell lines tested, with an additive effect in combination. Reduction in cell proliferation at low doses of nab-paclitaxel (10 nM), merestinib (100 nM), and their combination was 87%, 82%, and 94% (MKN-45, high phospho-c-Met expression), 59%, 50%, and 82% (SNU-1, low phospho-c-Met expression), and 53%, 19%, and 66% in gastric fibroblasts. Immunoblot analysis of merestinib treated MKN-45 cells revealed increased expression of pro-apoptotic proteins and decreased expression of phospho-c-Met, phospho-EGFR, phospho-IGF-1R, phospho-ERK, and phospho-AKT. In gastric fibroblasts, merestinib decreased phospho-ERK and increased pro-apoptotic protein expression. Phospho-c-Met and phospho-EGFR were not detected in SNU-1 immunoblots; however, phospho-ERK, phospho-VEGFR, and apoptotic protein expression increased after treatment. In MKN-45 xenografts, net tumor growth in control, nab-paclitaxel, merestinib, and combination groups was 503 mm3, 115 mm3, 91 mm3, and -9.7 mm3. Immunohistochemistry analysis of tumor cell proliferation and microvessel density corroborated tumor growth study results. Conclusions: These findings suggest that merestinib has strong antitumor activity in GAC and exhibits an additive effect when administered with nab-paclitaxel. These results provide compelling evidence that this therapeutic approach may lead to a clinically relevant combination to improve GAC patients’ survival.

Brachytherapy via a depot of biopolymer-bound 131I synergizes with nanoparticle paclitaxel in therapy-resistant pancreatic tumours.

Locally advanced pancreatic tumours are highly resistant to conventional radiochemotherapy. Here we show that such resistance can be surmounted by an injectable depot of thermally responsive elastin-like polypeptide (ELP) conjugated with iodine-131 radionuclides (131I-ELP) when combined with systemically delivered nanoparticle albumin-bound paclitaxel. This combination therapy induced complete tumour regressions in diverse subcutaneous and orthotopic mouse models of locoregional pancreatic tumours. 131I-ELP brachytherapy was effective independently of the paclitaxel formulation and dose, but external beam radiotherapy (EBRT) only achieved tumour-growth inhibition when co-administered with nanoparticle paclitaxel. Histological analyses revealed that 131I-ELP brachytherapy led to changes in the expression of intercellular collagen and junctional proteins within the tumour microenvironment. These changes, which differed from those of EBRT-treated tumours, correlated with the improved delivery and accumulation of paclitaxel nanoparticles within the tumour. Our findings support the further translational development of 131I-ELP depots for the synergistic treatment of localized pancreatic cancer.

A phase 1 trial of FID-007, a novel nanoparticle paclitaxel formulation, in patients with solid tumors.

3021 Background: FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. In addition to allowing the drug to remain in solution until it can enter a cancer cell, the PEOX nanoparticle preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. In xenograft studies, FID reduced or limited tumor growth in multiple tumor types including lung, gastric, breast, pancreatic, and ovarian cancer. FID was more effective at lower or comparable taxane doses with fewer side effects. We present the first-in-human trial of FID. Methods: The study is evaluating the safety, PK, and efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 125mg/m2 using a standard 3+3 dose escalation design. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and no more than 3 prior lines of cytotoxic therapy for advanced disease. Results: Twenty-five pts were treated across 6 dose levels. Median age was 62 (44-76). ECOG PS was 2 in 1 pt and 1 in 64%. Median number of cycles was 2 (1-16). There were 2 DLTs of grade 3 rash at 100 mg/m2. Given the transient nature of the rash and response to topical therapy, DLT definition was modified to exclude grade 3 rash that lasts ≤ 7 days and additional patients were treated at 100 mg/m2 which was deemed tolerable. There was 1 DLT of grade 3 neutropenia at 125 mg/m2. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts were rash (64%), alopecia (52%), pruritus (44%), anemia (44%) leukopenia, fatigue (40% each), dysgeusia, anorexia, nausea (32% each), and neutropenia (28%). Grade 3/4 TRAEs occurring in > 1 pt were anemia (20%), neutropenia, leukopenia, and maculopapular rash (16%). There were no treatment discontinuations due to toxicity. Twenty-two pts were evaluable for response by RECIST 1.1 with a PR rate of 14% (PR in pancreatic, biliary tract and NSCLC) and disease control rate of 59%. PK is linear and dose proportional. There is no paclitaxel accumulation after weekly dosing, and the t1/2 is between 18-26 hours. Conclusions: FID has a manageable safety profile with MTD not reached. Accrual is continuing at 125 mg/m2. PK is linear, dose proportional and comparable to that of nab-paclitaxel. There is preliminary evidence of anti-tumor activity in heavily pre-treated pts across different tumor types. Enrollment in dose escalation continues. Combination studies with immunotherapeutic agents are planned. Clinical trial information: NCT03537690.

Targeted dual inhibition of c-Met/VEGFR2 signalling by foretinib improves antitumour effects of nanoparticle paclitaxel in gastric cancer models.

Elevated expression of multiple growth factors and receptors including c‐Met and VEGFR has been reported in gastric adenocarcinoma (GAC) and thus provides a potentially useful therapeutic target. The therapeutic efficacy of foretinib, a c‐Met/VEGFR2 inhibitor, was determined in combination with nanoparticle paclitaxel (NPT) in GAC. Animal studies were conducted in NOD/SCID mice in subcutaneous and peritoneal dissemination xenografts. The mechanism of action was assessed by Immunohistochemical and Immunoblot analyses. In c‐Met overexpressing MKN‐45 cell‐derived xenografts, NPT and foretinib demonstrated inhibition in tumour growth, while NPT plus foretinib showed additive effects. In c‐Met low‐expressing SNU‐1 or patient‐derived xenografts, the foretinib effect was smaller, while NPT had a similar effect compared with MKN‐45, as NPT plus foretinib still exhibited an additive response. Median mice survival was markedly improved by NPT (83%), foretinib (100%) and NPT plus foretinib (230%) in peritoneal dissemination xenografts. Subcutaneous tumour analyses exhibited that foretinib increased cancer cell death and decreased cancer cell proliferation and tumour vasculature. NPT and foretinib suppressed the proliferation of GAC cells in vitro and had additive effects in combination. Further, foretinib caused a dramatic decrease in phosphorylated forms of c‐Met, ERK, AKT and p38. Foretinib led to a decrease in Bcl‐2, and an increase in p27, Bax, Bim, cleaved PARP‐1 and cleaved caspase‐3. Thus, these findings highlight the antitumour impact of simultaneous suppression of c‐Met and VEGFR2 signalling in GAC and its potential to enhance nanoparticle paclitaxel response. This therapeutic approach might lead to a clinically beneficial combination to increase GAC patients’ survival.

Abstract OT1-07-01: Phase 1/2 study of topical SOR007 (nanoparticle paclitaxel ointment) for cutaneous metastasis

Abstract Background: Cutaneous metastases are common in non-skin cancers, resulting in considerable morbidity, infection, pain, and negatively impacting quality of life. No standard of care exists for effective control of cutaneous metastases, which is a significant unmet need in oncology. Paclitaxel has shown effectiveness in the treatment of ovarian, breast, non-small cell lung, and pancreatic cancers and is approved by the United States Food and Drug Administration for the systemic treatment of many types of malignancies. We hypothesize that SOR007, or nanoparticulate paclitaxel ointment may be well tolerated and effective in the treatment of cutaneous metastases. Trial Design: This trial is a Phase 1/2, open-label study evaluating the safety, tolerability, and preliminary efficacy of three concentrations of SOR007 (0.15%, 1.0%, and 2.0%) ointment applied topically, twice daily, to non-melanoma cutaneous metastases during a 3+3 dose-ascending or dose expansion phase. Subjects will self-apply SOR007 ointment twice daily on Days 1 to 28, to a 50 cm2 area containing an eligible lesion. If a single dose limiting toxicity (DLT) is identified in the three subjects, an additional three subjects will be enrolled at the same dose level. If one or more DLT occur in the three additional subjects, dose escalation will stop and the prior dose level will be determined as the Maximum Tolerated Dose (MTD) and taken forward into the dose expansion phase. If no further DLT are identified, dose escalation will continue, until either a DLT is identified at a higher dose or the top dose of 2% is reached. Once DLT is determined, additional subjects will be enrolled in the expansion phase, to total up to 12 subjects at the top dose. Specific Aims: 1) The primary objective of this study is to determine preliminary safety and tolerability of topical SOR007. Secondary endpoints include: 2) evaluating preliminary efficacy based on RECIST criteria, photograph documentation of lesion size in longest diameter, and objective clinical response. 3) We will evaluate potential reduction in pain at the treatment area. 4) We will determine the peripheral blood pharmacokinetics of topical SOR007 applied to cutaneous metastases. Eligibility criteria: Male and female patients over the age of 18 with malignancies resulting in cutaneous metastasis originating from: breast, lung, head and neck, pancreatic, urinary bladder, prostate, testicular, ovarian, uterine, cervical, gastric, adrenal, thyroid, parathyroid cancers or other solid tumors which previously responded to taxane treatment are eligible to participate. Patients' last dose of any systemic non-taxane cytotoxic chemotherapy should be completed at least one day prior to the trial. Patients' last dose of any systemic taxane cytotoxic chemotherapy should be completed at least 4 weeks prior to the trial. Patients should be ECOG 0-2 with a minimum life expectancy of at least 3 months. Open or ulcerated wound(s) extending through the dermis are not eligible. Statistical methods: Data will be analyzed by descriptive statistics. Present accrual and target accrual: To date, we have enrolled 3 of a maximum of 24 subjects. Citation Format: Lang JE, Chawla S, Chang J, diZerega G, Cavanna-Mast RM, Savoie C, Lacouture M. Phase 1/2 study of topical SOR007 (nanoparticle paclitaxel ointment) for cutaneous metastasis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-07-01.

Different Nanoformulations Alter the Tissue Distribution of Paclitaxel, Which Aligns with Reported Distinct Efficacy and Safety Profiles.

Previous studies have shown that different paclitaxel formulations produce distinct anticancer efficacy and safety profiles in animals and humans. This study aimed to investigate the distinct pharmacokinetics and tissue distribution of various nanoformulations of paclitaxel, which may translate into potential differences in safety and efficacy. Four nanoparticle formulations ( nab-paclitaxel, mouse albumin nab-paclitaxel [m -nab-paclitaxel], micellar paclitaxel, and polymeric nanoparticle paclitaxel) as well as solvent-based paclitaxel were intravenously administered to mice. Seventeen blood and tissue samples were collected at different time points. The total paclitaxel concentration in each tissue specimen was measured with liquid chromatography-tandem mass spectrometry. Compared with solvent-based paclitaxel, all four nanoformulations demonstrated decreased paclitaxel exposure in plasma. All nanoformulations were associated with paclitaxel blood-cell accumulation in mice; however, m- nab-paclitaxel was associated with the lowest accumulation. Five minutes after dosing, the total paclitaxel in the tissues and blood was approximately 44% to 57% of the administered dose of all paclitaxel formulations. Paclitaxel was primarily distributed to liver, muscle, intestine, kidney, skin, and bone. Compared with solvent-based paclitaxel, the different nanocarriers altered the distribution of paclitaxel in all tissues with distinct paclitaxel concentration-time profiles. nab-paclitaxel was associated with increased delivery efficiency of paclitaxel in the pancreas compared with the other formulations, consistent with the demonstrated efficacy of nab-paclitaxel in pancreatic cancer. All the nanoformulations led to high penetration in the lungs and fat pad, which potentially points to efficacy in lung and breast cancers. Micellar paclitaxel and polymeric nanoparticle paclitaxel were associated with high paclitaxel accumulation in the heart; thus, the risk of cardiovascular toxicity with these formulations may warrant further investigation. The solvent-based formulation was associated with the poorest paclitaxel penetration in all tissues and the lowest tissue-to-plasma ratio. The different nanocarriers of paclitaxel were associated with distinct pharmacokinetics and tissue distribution, which largely align with the observed efficacy and toxicity profiles in clinical trials.

Cyclic Voltammogram of Paclitaxel Nanoparticles

Background: Successful nanoparticles formulations include Abraxane® (an albumin bound nanoparticle paclitaxel), Genexol-PM® (a polymer bound nanoparticle paclitaxel), and Doxil®. At LipoMedics we have developed a unique nanomedicinization process of water insoluble drug for intravenous administration using combination of solvents and polymers. The polymers can be simple phospholipid or synthetic diblock polymer or complex protein such as albumin. Electrochemistry was used to understand the molecular organization of these nanoparticles and biosensor built to support the in process monitoring of this pharmaceutic. Materials and Methods: Nanoparticle synthesis was conducted using a two step method whereby the drug is first emulsified in presence of solvent and then nanofabricated in presence of polymer. Nanoparticle size and zeta potential were measured using a Malvern ZS DLS system. The formulation was subjected to serial filtration using 1.2µm, 0.8µm, 0.45µm and 0.2µm syringe filters. The drug incorporation/loading was measured using ELISA. Electrochemical properties of the formulation were measured using screen printed carbon nanotube (CNT) electrodes from DropSens and a PGSTAT204 Autolab Potentiostat from Metrohm. The drug being evaluated in this study is paclitaxel- a water insoluble drug that can only be solubilized in Cremophor EL for intravenous administration. Only nanomedicinization allowed paclitaxel to be formulated without solvent. Results:A series of stable nanomedicinized paclitaxel formulations were created using chloroform or ethanol as solvent and phospholipid or albumin as polymer. Each formulation exhibited a distinct cyclic voltammetry (CV) scan. The CV scan was highly dependent on the polymer used. Monolayer and bilayer phospholipids behaved similarly as polymer with or without paclitaxel. Increasing the loading of these phospholipid nanoparticles caused a shift from profiles of high capacitance material to profiles of low capacitance material. Discussion: Capacitance of a carbon-based electrode consists of two major components: the electrical double layer capacitance due to the electrostatic attraction of charged carbon surfaces to electrolyte ions and the pseudocapacitance due to the Faradic reactions of electroactive species on the carbon surfaces. During electrochemical evaluations, the nanoparticles were treated as ionic liquid capacitance material. Low capacitance is suggestive of weakened charge accumulation in the electrode - electrolyte interface which depends on the mesoporosity and electrolyte accessibility of the capacitive material.

Abstract P5-16-29: Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: A meta-analysis

Abstract Background: Nanoparticle albumin-bound paclitaxel (nab-Paclitaxel), a novel solvent-free taxane-based regimen, was hypothesized to have enhanced drug transport to tumors, shorter infusion schedules and no need for premedication. The value of nab-Paclitaxel in neoadjuvant systemic therapy (NST) for breast cancer remains uncertain. We performed a meta-analysis to assess efficacy and toxicity of nab-Paclitaxel compared to conventional taxane regimens (paclitaxel, docetaxel) within randomized clinical trials. Methods: A systematic search was performed using the medical subject heading (MeSH) terms ''breast neoplasms'', as well as (1) breast cancer; AND (2) nab-Paclitaxel OR nanoparticle paclitaxel; AND (3) neoadjuvant OR preoperative OR primary systemic in both Pubmed databases and proceedings of oncologic meetings including ASCO, ESMO and SABCS. Pooled rates of pathological complete response(pCR), odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed-effect or random-effect model to determine the effect of neoadjuvant nab-paclitaxel. Results: Twenty-one studies with 2357 patients were included, 3 of which (GeparSepto[1], ETNA[2], Showa trial[3]) were randomized clinical trials. The aggregate pCR rate (ypT0/is ypN0) was 32% (95% CI 25-38%) in unselected breast cancer patients and was 14%(95% CI 11-17%), 41%(95% CI 38-45%), 54%(95% CI 43-66%) in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-), triple negative breast cancer(TNBC), HER2+ patients, respectively. Within the HER2+ population, pCR rate was 61%(95% CI 47-74%) for HR- and 40%(95% CI 28-52%) for HR+ tumors. Regarding randomized clinical trials, the probability of achieving pCR was significantly higher in the nab-paclitaxel group than in the conventional taxanes group (OR=1.383, 95%CI 1.141-1.676, p=0.001). A funnel plot of the effect size for each randomized trial against the precision showed no asymmetry, which indicating no potential publication bias. In the safety analysis (GeparSepto[1], ETNA[2]), hematological toxic effects were generally equivalent in nab-paclitaxel and paclitaxel group. For non-hematological toxic effects, all grades and grade≥ 3 peripheral sensory neuropathy occurred more frequently with nab-paclitaxel compared to paclitaxel (all grades, OR=2.090, 95%CI 1.016-4.302, p=0.045; grade≥ 3, OR=3.766, 95%CI 2.324-6.100, p<0.001). Hypersensitivity was more common with paclitaxel than nab-paclitaxel at any grade and grade≥ 3. Other non-hematological toxic effects did not significantly differ between two groups. Conclusion: nab-Paclitaxel is an effective antitumor drug in NST of breast cancer, especially for TNBC and HER2+ tumors, in terms of pCR. Exchange of nab-Paclitaxel for conventional taxanes could significantly improve pCR rate with reasonable toxicities. Clinical trial information: 1.Lancet Oncol.2016,17:345-56.; 2.J Clin Oncol.2016,34(suppl; abstract 502).; 3.J Clin Oncol.2015,33(suppl; abstract 136). Citation Format: Zong Y, Wu J, Shen K. Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: A meta-analysis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-29.

Abstract 2193: Stabilityof injectable phospholipid nanoparticles loaded with paclitaxel: influence oflipid composition, drug concentration, storage temperature, lyophilization, andadditives

Abstract Paclitaxel is one of the most effective chemotherapeutic drugs for solid tumors including breast, lung and ovarian cancers. It has been formulated as a nanoparticle formulation, Abraxane, to improve its solublity (0.35-0.7 μg/mL) and to avoid the use of harmful solvents like cremophor EL. We previously reported the next-generation Abraxane - Cynviloq - a polymeric micelle paclitaxel formulation which uses a chemical polymer instead of biological polymer to stabilize the nanoparticle [1]. Here we investigate and report the use of phospholipids instead of a chemical polymer for the creation of the next-generation Abraxane. The effect of lipid composition on drug loading and physical stability of paclitaxel-loaded lipid-coated nanoparticle formulation was evaluated before and after lyophilization. The nanoparticles were prepared by microfluidization-solvent evaporation method. The formulation parameters included type of phospholipids, phospholipid fatty acid chain length, ratio of phospholipid and lysophospholipid combination, and drug-phospholipid ratio. The process parameters such as microfluidization pressure and number of microfluidization cycles were studied and their impact on drug loading, particle size and physical stability were evaluated. The short-term stability evaluation of nanoparticles prepared with different phospholipid ratios demonstrated that 4:1 as the optimum phospholipid-lysophospholipid ratio to achieve a loading of more than 60% paclitaxel with particle size of approximately ∼200nm. The nanoparticle size increased with an increase of carbon chain length of the phospholipid fatty acid, but no significant trends were observed for drug loading with changes in microfluidization pressure or number of cycles. The stability of the formulation was evaluated at different temperatures before and after lyophilization. The optimization of phospholipid composition, drug-lipid ratio, process parameters and additives for stability on lyophilization led to a physically stable paclitaxel-loaded phopholipid-coated nanoparticulate formulation that maintains size, charge and particulate integrity during storage. Phospholipid bound paclitaxel nanoparticle was successfully manufactured in lab scale with the desired properties. Scaling up and additional work-up for clinical evaluation is being evaluated. Reference: 1. Motamed K, Goodman Y, Hwang L, Hsiao C, Trieu V. (2014). IG-001 - A non-biologic nanoparticle paclitaxel for the treatment of solid tumors. J Nanomater Mol Nanotechnol 3:1. doi:10.4172/2324-8777.1000136. Citation Format: Shrada Prabhulkar, Gary Williams, Steve Miller, Zachary Yim, Walter McConathy, Tapas De. Stabilityof injectable phospholipid nanoparticles loaded with paclitaxel: influence oflipid composition, drug concentration, storage temperature, lyophilization, andadditives. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2193.

Abstract 5532: Polymeric albumin-free paclitaxel intraperitoneal therapy demonstrates superior efficacy over nab-paclitaxel intravenous therapy in a mouse model of metastatic ovarian cancer

Abstract Introduction: The polymeric albumin-free micellar formulation of paclitaxel, Cynviloq™, is being developed as the next generation nanoparticle paclitaxel for treatment of solid tumor indications. Using albumin-bound nab-paclitaxel (nab-PTX) as comparator in in vitro dissolution and mouse PK studies, we recently reported a 10-fold higher nanoparticle stability in serum-free media and a 10-fold increased peritoneal paclitaxel levels for Cynviloq vs. nab-PTX as early as 1 hour post IP administration at 30 mg/kg. Moreover, since antitumor efficacy of nab-PTX after IV and IP administrations was recently shown to be equivalent in a peritoneal metastatic gastric cancer model, we set out to compare the efficacy of IV nab-PTX vs. IP Cynviloq in a peritoneal metastatic model of ovarian cancer. Methods: Five to six-weeks old athymic female nu+/nu+ mice were injected IP with 2×106 IGROV1 human ovarian cancer cells/100 μL saline. Mice were randomized into five experimental groups and one saline control group (n = 10-13) 7 days post tumor inoculation with the day of injection assigned as Day 0. nab-PTX was administered IV at 15 or 30 mg/kg, whereas Cynviloq was administered IP at 15, 30 and 60 mg/kg/day according to a qdx5 dosing regimen. Tumor-bearing mice were monitored twice weekly up to 12 weeks for weight loss and girth increase. Study endpoints included quantification of intraperitoneal tumor nodule size and number of nodules, incidence and volume of collected ascites as well as overall survival. Statistical analyses performed included Chi square test, ANOVA and unpaired Student's t-test. Results: Treatments with either IP Cynviloq or IV nab-PTX were well tolerated and significantly (P<0.05) increased the median survival of mice compared to untreated controls. However, analysis of Kaplan-Meier survival curves revealed that IP Cynviloq treatments conferred significant survival advantage over IV nab-PTX at 15 and 30 mg/kg doses (P = 0.0011 and 0.0387, respectively). Cynviloq-treated cohorts also displayed significant (P = 0.0057) dose-dependent survival advantage relative to the nab-PTX-treated cohorts (P = 0.0454). Consistent with these findings, mice treated with 15 and 30 mg/kg IP Cynviloq showed significantly decreased intraperitoneal tumor burden scores (P = 0.014 and 0.025, respectively). However, significant decreases in ascitic fluid volumes were only observed in mice treated with 15 mg/kg IP Cynviloq (P = 0.006). Conclusions: Collectively, our data strongly supports the notion that compared to IV-administered nab-PTX, IP delivery of Cynviloq results in improved efficacy without any additional toxicity in a metastatic model of ovarian cancer. Hence, further development of IP-administered Cynviloq in the treatment of indications with malignant ascites, including ovarian and gastric cancers, are therefore warranted. Citation Format: Kouros Motamed, Neveen Said. Polymeric albumin-free paclitaxel intraperitoneal therapy demonstrates superior efficacy over nab-paclitaxel intravenous therapy in a mouse model of metastatic ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5532. doi:10.1158/1538-7445.AM2015-5532

Abstract 5414: IG-001 potential as intraperitoneal therapy for ovarian cancer

Abstract Introduction: nab-paclitaxel–a Cremophor-free, albumin-bound, nanoparticle form of paclitaxel–though a breakthrough in paclitaxel formulation, has inherent problems associated with any biologics. IG-001 (Cynviloq/Genexol-PM), a polymeric albumin-free micellar formulation utilizes biodegradable di-block copolymers composed of methoxy poly (ethylene glycol)-poly (lactide) to form nanoparticles with paclitaxel and is being developed as the next generation nanoparticle paclitaxel. Its target indications are solid tumors such as Breast, NSCLC, Ovarian, Bladder and Pancreatic cancers, taking advantage of its ability to rapidly deliver paclitaxel to the targeted tissue via albumin-mediated transport, as previously described for nab-paclitaxel. Herein, we report preclinical and dissolution stability of IG-001 in comparison to nab-paclitaxel in the ovarian cancer setting. Methods: Preclinical PK parameters (HL, Tmax, AUCinf, Vz and CL) of the two formulations were compared following bolus IV and IP injections (30 mg/kg) in mice. Blood paclitaxel concentration was quantified using LC/MS/MS method and PK parameters were obtained using the Phoenix PK program (Pharsight, CA). Dissolution studies of nab-paclitaxel and IG-001 were performed using the drug products reconstituted in saline and diluted in PBS or plasma. Particle stability was monitored by dynamic light scattering using the Malvern Nanosizer. Results: IG-001 exhibited conditional stability, wherein stability was high in PBS and Lactated Ringer's solution but very low in plasma. In contrast, nab-paclitaxel exhibited the expected instability in both plasma and PBS. Across multiple experiments, there was about a 10-fold enhancement of particle stability in serum-free matrices. This suggests that IG-001 may have a PK advantage over nab-paclitaxel when administered as saline-reconstituted solution into the peritoneal cavity for the treatment of ovarian cancer. Therefore, a PK study was performed in mice with drugs administered IP and IV. The bolus IV injection studies in mice revealed almost identical PK parameters for the two formulations. However, IP injection studies indicated about a 10-fold enhanced paclitaxel levels for IG-001 vs. nab-paclitaxel up to 1 hour post administration. Thereafter, it was not possible to determine IP paclitaxel levels due to complete absorption of the administered drug solution. Conclusions: Collectively, our data strongly supports the notion that the conditional stability of IG-001 would confer an advantage in ovarian indication wherein the drug is administered IP as a saline reconstituted drug solution. It also suggests that the observed preferential peritoneal accumulation of paclitaxel when Taxol was administered may not be applicable to nab-paclitaxel due to the absence of Cremophor-EL as a sequestering agent in the peritoneal cavity. Citation Format: Kouros Motamed, Rosemary Kim, Hyunjoung Yang, Vuong Trieu. IG-001 potential as intraperitoneal therapy for ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5414. doi:10.1158/1538-7445.AM2014-5414

Abstract CT316: IG-001 phase 4 data in Korea: Safety and efficacy

Abstract Study Purpose: IG-001, utilizes biodegradable di-block copolymers composed of methoxy poly (ethylene glycol)-poly (lactide) to form nanoparticle (NP) with paclitaxel and is being developed as the next generation NP Paclitaxel. IG-001 was launched as Genexol-PM in Korea in 2007 and the post-marketing surveillance (PMS) for breast cancer has been completed. This was a PMS study of IG-001 in patients with locally recurrent or metastatic breast cancer conducted to investigate the incidences & types of adverse events (AEs) including unexpected and serious AEs in clinical use. The study was also intended to monitor changes in the incidences and types of AEs, to assess clinical factors affecting safety and efficacy in this setting. Methods: The study was conducted at 12 medical institutions in Korea from 2007 to 2010. 186 subjects were enrolled and surveillance data was collected during this period. The starting dose of IG-001 was 300 mg/m2 with possible dose reductions in 2 stages based on hematological and non-hematological toxicities (except alopecia) to 240 mg/m2 and 190 mg/m2. IG-001 was administered as an IV infusion over 3 hours. Results: In subjects with measurable disease at enrollment, subject responses were determined by comparing the tumor dimensions before & after treatment using either the WHO standard or RECIST criteria. In subjects with no measurable tumors at enrollment, response was determined by assessing the clinical condition of the subject. The “best overall response” was used to categorize response. For subjects with measurable disease, complete response (CR) and partial response (PR) were classified as efficacious while stable disease (SD), progressive disease (PD) & not assessable disease were classified as inefficacious. The results showed that 36/148 evaluable subjects (24.32%) responded to study drug treatment with PR and were judged efficacious. SD occurred in 53 subjects (35.81%) and PD observed in 58 subjects (39.19%). 1 subject (0.68%) was not assessable and no CR observed. The background factors analyzed for possible correlations with efficacy included age, illness duration, disease stage, concurrent disease, medical history, total number of treatment cycles, mean dose of study drug per cycle and concomitant anticancer therapy. One factor correlated with efficacy was the total number of drug treatment cycles (p < 0.0001). The efficacy was 0% in the 53 subjects who received 3 or fewer cycles of treatment and 42.47% in the 73 subjects who received 6 or more cycles (31/73). 21 subjects (11.29%) reported a total of 34 serious AEs. The most frequent were neutropenia (1.61%), febrile neutropenia (1.61%), headache (1.61%), vomiting (1.08%), fever (1.08%), dyspnea (1.08%) and tachycardia (1.08%). Most of these were secondary to expected toxicities of the study drug. Conclusions: In this PMS study of IG-001 in patients with breast cancer, the study drug was well tolerated with an excellent safety profile even though most of these patients had extensive prior chemotherapy. Citation Format: Larn Hwang, Caleigh Douglass, David Nam, Vuong Trieu. IG-001 phase 4 data in Korea: Safety and efficacy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT316. doi:10.1158/1538-7445.AM2014-CT316

P0157 Preclinical evaluation of NBN-paclitaxel in pancreatic cancer xenograft models

<h3>Background</h3> Despite being the standard of care, gemcitabine has limited clinical benefits in pancreatic cancer. The goal of this study was to determine whether non-biological, nanoparticle paclitaxel (NBN-Pac/IG-001) exhibits sufficiently robust preclinical activity to qualify for clinical development. <h3>Methods</h3> We tested NBN-paclitaxel in various pancreatic cancer cell lines and xenograft models. <h3>Findings</h3> The maximum-tolerated dose of NBN-paclitaxel was calculated to be 60mg/kg versus 20mg/kg for standard paclitaxel. NBN-paclitaxel was generally more efficacious than standard paclitaxel or gemcitabine. In vitro, enhanced activity was shown by NBN-paclitaxel as compared to standard paclitaxel or gemcitabine against four pancreatic cell lines (MIA Paca-2, Capan-1, PANC-1, and AsPC-1). This increased activity was also demonstrated in vivo in female athymic nude mice using two pancreatic cancer cell lines (MIA PaCa-2 and PANC-1) as well as in male nude BALB/c mice following the orthotopic (pancreatic) implantation of AsPC-1 pancreatic cancer cells. NBN-paclitaxel produced superior anti-tumour activity against the human pancreatic carcinoma xenograft MIA PaCa-2. The rank order (% complete regression) was as follows: NBN-paclitaxel (60, 40, 25mg/kg), standard paclitaxel (25mg/kg), and gemcitabine (140mg/kg). NBN-paclitaxel produced a marked, dose-related anti-tumour effect in the PANC-1 xenograft model, with complete remission in all animals at 50mg/kg per dose and significant partial remission at 20mg/kg per dose. Overall, NBN-paclitaxel was shown to be more efficacious than either standard paclitaxel or gemcitabine, at equitoxic dose. NBN-paclitaxel produced dose-dependent primary tumour suppression (41%, 37% and 26%) and reduced the number of metastasised tumour nodules (22%, 19% and 13%) in the AsPC-1 metastasis model at doses of 20, 35, and 50mg/kg, respectively. Anti-tumour activity of NBN-paclitaxel at 50mg/kg was superior to standard paclitaxel and gemcitabine at an equitoxic dose. <h3>Interpretation</h3> The preclinical data suggest that NBN-paclitaxel could be superior to standard paclitaxel at an equitoxic dose. The data support further development of NBN-paclitaxel.

75P - IG-001—A Non-Biologic Micellar Paclitaxel Formulation for the Treatment of Metastatic Breast Cancer

Introduction: IG-001 (Genexol-PM), utilizes biodegradable di-block copolymers composed of methoxy poly (ethylene glycol)-poly (lactide) to form micellar nanoparticles with paclitaxel containing a hydrophobic core and a hydrophilic shell and is being developed as the next generation nanoparticle paclitaxel. Its target indications are solid tumors such as Metastatic Breast Cancer (MBC), Lung, Ovarian, Bladder, Pancreatic and Melanoma. Herein, we have provided the results of clinical experience with IG-001 in MBC available to date through summaries of two completed Phase 2 studies, an ongoing Phase 3 study and a completed post-marketing surveillance (PMS) study.

IG-001 - A Non-Biologic Nanoparticle Paclitaxel for the Treatment of Solid Tumors

IG-001 - A Non-Biologic Nanoparticle Paclitaxel for the Treatment of Solid Tumors nab-paclitaxel (Abraxane®)—a Cremophor-free, albumin-bound, nanoparticle form of paclitaxel—though a breakthrough in paclitaxel formulation, has inherent problems associated with any biologics. IG-001 (Genexol-PM®), a polymeric micellar formulation forms nanoparticles with paclitaxel containing a hydrophobic core and a hydrophilic shell and is being developed as the next generation nanoparticle paclitaxel. Its target indications are solid tumors including Breast, Lung, Ovarian, Bladder, Melanoma and Pancreatic cancers. Similar to nab-paclitaxel, due to its very fast dissolution in plasma, high tumor/plasma ratio, and dose-proportional PK, IG-001 is a superior alternative to Taxol®. Moreover, despite a lack of serum albumin in its formulation, IG-001 takes full advantage of its ability to rapidly deliver paclitaxel to the targeted tissue via an albuminmediated transport, as previously described for nab-paclitaxel.

Sequential Targeted Delivery of Paclitaxel and Camptothecin Using a Cross-Linked “Nanosponge” Network for Lung Cancer Chemotherapy

The applicability of a HVGGSSV peptide targeted "nanosponge" drug delivery system for sequential administration of a microtubule inhibitor (paclitaxel) and topoisomerase I inhibitor (camptothecin) was investigated in a lung cancer model. Schedule-dependent combination treatment with nanoparticle paclitaxel (NP PTX) and camptothecin (NP CPT) was studied in vitro using flow cytometry and confocal imaging to analyze changes in cell cycle, microtubule morphology, apoptosis, and cell proliferation. Results showed significant G2/M phase cell cycle arrest, changes in microtubule dynamics that produced increased apoptotic cell death and decreased proliferation with initial exposure to NP PTX, followed by NP CPT in lung cancer cells. In vivo molecular imaging and TEM studies validated HVGGSSV-NP tumor binding at 24 h and confirmed the presence of Nanogold labeled HVGGSSV-NPs in tumor microvascular endothelial cells. Therapeutic efficacy studies conducted with sequential HVGGSSV targeted NP PTX and NP CPT showed 2-fold greater tumor growth delay in combination versus monotherapy treated groups, and 4-fold greater delay compared to untargeted and systemic drug controls. Analytical HPLC/MS methods were used to quantify drug content in tumor tissues at various time points, with significant paclitaxel and camptothecin levels in tumors 2 days postinjection and continued presence of both drugs up to 23 days postinjection. The efficacy of the NP delivery system in sequential treatments was corroborated in both in vitro and in vivo lung cancer models showing increased G2/M phase arrest and microtubule disruption, resulting in enhanced apoptotic cell death, decreased cell proliferation and vascular density.

Abstract B67: IG-001: A non-biologic nanoparticle paclitaxel for the treatment of ovarian cancer

Abstract Introduction: IG-001(Genexol-PM), like nab-paclitaxel, is a polymer bound nanoparticle paclitaxel. IG-001 utilizes biodegradable di-block copolymer composed of methoxy poly (ethylene glycol)-poly (lactide) to form nanoparticles with Paclitaxel containing hydrophobic core and a hydrophilic shell. IG-001 is being developed for difficult to perfuse hypoxic tumors such as pancreatic cancer and ovarian cancer. Methods: Clinical efficacy was evaluated across multiple cancer indications including metastatic breast cancer (MBC), non small cell lung cancer (NSCLC), pancreatic cancer and ovarian cancer. Phase I ovarian trial design: six patients/dose level were treated with IG-001 at 220, 260, and 300 mg/m2. Phase II ovarian trial design: randomized, two-arm trial, primary advanced epithelial ovarian cancer consisting of 100 pts (50/each arm). Control Arm: Solvent based paclitaxel 175mg/m2 IV + Carboplatin 5 AUC IV, 3 weeks, 6 cycles and Experimental Arm: IG-001 260mg/m2 IV + Carboplatin 5 AUC IV 3 weeks, 6 cycles. Phase III ovarian trial design- planning phase to consist of therapeutic drug monitoring and biomarker testing. Results: Clinical trials conducted with IG-001 demonstrated significant antitumor activities comparable to historical data for Abraxane. Across three cancer indications (MBC, NSCLC, and Pancreatic Cancer), IG-001 was more active than historical Taxol. Since Pancreatic Cancer is known to be poorly-perfused, IG-001 activity in this indication is consistent with it being able to penetrate poorly-perfused tumors. Conclusions: IG-001 is effective across multiple cancer indications. Clinical development of IG-001 in ovarian cancer is ongoing. Phase I data was encouraging and phase II data forthcoming. IG-001 could be considered to be superior to Cremophore based paclitaxel because of the possibilities of delivering higher paclitaxel dose without additional toxicities. Phase III trial design incorporating therapeutic drug monitoring and biomarker testing should further improve on IG-001 clinical activities. Citation Format: Larn Hwang, Catherine Cheng, Vuong Trieu. IG-001: A non-biologic nanoparticle paclitaxel for the treatment of ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B67.

Clinical and economic implications of the use of nanoparticle paclitaxel (Nanoxel) in India

Paclitaxel (Taxol), one of the most commonly used chemotherapeutic agents, is poorly soluble in water and requires cremophor, which often causes infusion reactions, as a solvent. Nanoxel, a nanoparticle formulation of the taxane, has been approved by the Indian regulatory authority. In the present article, we aim to describe the experience with the use of Nanoxel in India and its clinical and economic implications. We present three retrospective series in a common practice environment and an economic model. The first series shows no reactions in 596 Nanoxel infusions; the second series shows comparable adverse events other than infusion reactions between 83 patients who received Nanoxel and 32 treated with conventional paclitaxel. The third reveals comparable clinical outcomes for 51 patients treated with Nanoxel or conventional paclitaxel for gastroesophageal tumors. Finally, we describe an economic model which estimates savings of 21 580 Indian rupees per cycle with Nanoxel vis-à-vis conventional paclitaxel in the treatment of solid tumors in India. In conclusion, in an era in which the greatest challenge we face as medical oncologists is how to conciliate hard-won and incremental--but small--improvements in survival with exponentially rising drugs costs, it is refreshing to see a potential new formulation of a commonly used drug that may actually generate cost-savings while improving clinical outcomes and patient well-being. Further studies are clearly warranted to determine the optimal dose and schedule for Nanoxel as well as its comparative effectiveness to cremophor-based paclitaxel.